Transcript The Neuroscience of Psychiatry

Anti-Depressant Medications
Brian Ladds, M.D.
Outline
• Earliest meds:
– MAOI
– TCA
• Neurotransmitter emphasized: NOR
• More recent meds:
– SSRI
• Neurotransmitter emphasized: SE
Discovery of Anti-Depressants
• Historical Serendipity:
– An early anti-TB medication was noted
incidentally to have:
• anti-depressant effects
• and was found to inhibit MAO enzyme as one of its
properties
– Since making more monoamines available
alleviated depression, perhaps the basis of
depression is a deficiency of one or another
monoamine in the brain
Monoamines and Depression
• For many decades the principal monoamine
thought to be most relevant in depression
was norepinephrine.
• In the last decade, the role of another
monoamine, serotonin, has also been
emphasized.
Neurotransmitters
• 3 principal types of neurotransmitters
– monoamine neurotransmitters (MA)
– amino acid neurotransmitters
– neuropeptide neurotransmitters
Monoamine Neurotransmitters
• Catecholamines
– dopamine
– norepinephrine
• tyrosine hydroxylase enzyme
– synthesizes l-dopa from tyrosine
– rate-limiting step (usually saturated )
• Serotonin
• Acetylcholine
• (Histamine)
Monoamine Neurotransmitters
• Monoamine neurotransmitters comprise only a
small percentage of neurons (vs. amino acid
neurotransmitters), but:
• Monoamines may regulate the balance of:
– the excitatory actions of glutamate and the inhibitory
actions of GABA
• The receptor sites for the monoamine
neurotransmitters are involved in many psychiatric
disorders
Monoamine Neurotransmitters
• The neurons that produce monoamines
originate in nuclei of the brainstem (or basal
forebrain) and project widely to the cortex,
where they release the neurotransmitters.
Norepinephrine Pathways
• Locus coeruleus in pons
• -> inervation to the forebrain
Life Cycle of the Monoamine
Neurotransmitters
• Synthesis:
– from simple precursors (tyrosine, tryptophan,
choline)
• Storage:
– stored in terminal pre-synaptic vesicles
• Release:
– into synaptic cleft
• Site of Action:
– act on post-synaptic receptors and elsewhere
• Inactivation
Monoamine Neurotransmitters:
Inactivation
• Inactivation:
– primarily via re-uptake back into the presynaptic nerve terminal and then recycled
– distinct “re-uptake transporters” (transmembrane proteins) for:
• dopamine vs. norepinephrine vs. serotonin
– and also by degradation by intra-cellular (and
extra-cellular) enzymes
Monoamine Oxidase Enzyme
• Monoamine oxidase (MAO) enzyme
– on external membrane of mitochondria
– catabolizes (or degrades) monoamines in the
nerve terminal cytosol (unprotected by vesicles)
• MAOA breaks down serotonin and norepi
• MAOB breaks down dopamine
MAO Inhibitors (MAOI)
• Examples: phenelzine (Nardil) or
tranylcypromine (Parnate)
• Irreversibly inhibit MAO enzyme
– Therefore takes 2 weeks after stopping the
MAOI to replenish new MAO enzyme
• Increase the availability of monoamines
– such as norepinephrine and serotonin, which
are thought to be decreased in depression
MAOI: Side Effects
• Tyramine Hypertensive Crises
– tyramine: contained in aged cheese, smoked
meats, certain wines
– is sympathomimetic and causes release of
norepi from sympathetic terminals, which in the
presence of MAOI can cause acute
hypertensive crises and stroke
MAOI: Side Effects
• Medication Interactions
– hypertensive crises with sympathomimetic
medications (as with tyramine)
– hyperthermia, e.g. with meperidine (Demerol)
(as in the case of Libby Zion)
• Other side effects
– as with TCA’s
Tri-cyclic Anti-depressants
• Tri-cyclic anti-depressants (TCA):
• Block re-uptake of monoamines, especially
NE (and some block to a lesser extent SE)
– the therapeutic mechanism of action
Anti-Depressants: Efficacy
• 2/3 respond
• Not a euphoriant or stimulant among people
who are not depressed
Anti-Depressants: Time Course
• Time course: 2-4 weeks delay of therapeutic
effect.
• Possibly due in part to:
– gene expression and the synthesis of new
structures & synapses
– down-regulation
A Theory of Down-Regulation
MAOI and TCA are thought to bring about an antidepressant effect by:
• making more norepinephrine available in the
synaptic cleft,
• thereby leading to the down-regulation of the postsynaptic adrenergic receptors
• restoring them to their normal number and
function.
Tri-cyclic Anti-depressants:
Side Effects
TCA also block post-synaptic:
• Histamine receptors
– causing sedation, weight gain
• Adrenergic receptors
– causing hypotension, dizziness
• Ach receptors
– causing anti-cholinergic side effects
Anti-cholinergic Side Effects
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Blurred vision
Urinary retention
Constipation
Dry mouth
(Confusion)
TCA and Risk of Overdose
• Can be fatal in overdose
Tri-cyclic Anti-depressants
• Some TCA’s and their side effect profile:
– Imipramine: one of the earliest, highly effective
but many side effects
– Desipramine: a metabolite of IMI, only blocks
re-uptake of NE (not SE); it is the least anticholinergic TCA
– Nortriptyline: least likely TCA to cause blood
pressure changes
– Others: amitriptyline, doxepin, amoxapine
Serotonin
Serotonin
• 5-HT (Hydroxy-tryptamine) = Serotonin
• synthesized from essential amino acid
tryptophan
• the rate-limiting enzyme not usually
saturated
– therefore increased levels of precursors cause
increased synthesis of serotonin
• (but dietary supplements of tryptophan not very
effective AD and have had contaminants)
Serotonin Pathways
• Serotonin
– several nuclei in the dorsal raphe in the midbrain
– projects to striatum, hypothalamus, and neocortex
Inactivation of Serotonin
• Inactivation via pre-synaptic re-uptake
• This re-uptake transport process is inhibited
by some anti-depressants
– TCA: imipramine (non-selective)
– SSRI: fluoxetine (Prozac), paroxetine (Paxil),
sertraline (Zoloft), citalopram (Celexa)
SSRI
• “Selective Serotonin Re-uptake Inhibitors”
– probably as effective as TCA in most sub-types
of depression
• most are structurally unrelated to TCA’s
– minimal anti-cholinergic or cardio-vascular side
effects
– safe in overdose
Serotonin Receptors
• Serotonin receptors (~ 13)
– 5HT-1
– 5HT-2
– 5HT-3
SSRI: Side Effects
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GI upset
weight loss
insomnia, jitteriness
sexual dysfunction (less libido, ED)
Other Anti-Depressants
• There are many other anti-depressants,
some with different mechanism of actions,
or combinations of receptor effects and side
effect profiles
– mirtazapine (Remeron)
• alpha-2 antagonist; also with 5HT-2, 5HT-3 and
histamine antagonist properties
– buproprion (Wellbutrin)
• NE and DA reuptake inhibitor
Uses of Anti-Depressants
• Depression
– Dysthymia ?
• Anxiety Disorders
– Panic Disorder
– OCD
• Eating disorders
• Pain
• PTSD